HER2-low across solid tumours: different incidences and definitions

Antibody-drug conjugates, particularly trastuzumab deruxtecan (T-DXd), have emerged as effective therapies for various solid tumours. Clinical trials show that T-DXd improves survival in both HER2-positive and HER2-low breast cancer patients. Additionally, it improves survival in HER2-positive gastro-oesophageal cancer and elicits objective responses in HER2-low tumours. Responses have also been noted in lung and gynaecological cancers with HER2 expression, although subgroup analyses for HER2-low cases are lacking. This review assesses HER2 protein expression levels and gene amplification across solid tumours where T-DXd shows potential benefits. We focus on the accuracy and limitations of HER2 testing methods, particularly for identifying HER2-low cancer. A semi-systematic approach was employed, searching EMBASE, Medline, Cochrane, and PubMed databases. We calculated median incidences of HER2-positive, HER2-low, and HER2-0 by immunohistochemistry (IHC), and HER2 amplification by in situ hybridisation (ISH). A total of 144 studies were included, covering breast (n=57), gastro-oesophageal (n=33), lung (n=17), gynaecological (n=24), and various other carcinomas (n=13). The median incidences of HER2-low were 52%, 16%, 58%, and 17% in breast, gastro-oesophageal, endometrial, and ovarian cancers, respectively, with unknown incidences in lung and cervical cancers. Factors influencing HER2-low detection include tumour heterogeneity, antibody clones, observer variability, and lack of validated scoring criteria. Given the significant proportion of HER2-low cases, many patients could benefit from T-DXd, but limitations in detection accuracy necessitate further research and standardisation in diagnostic methods and criteria to advance the clinical utility of T-DXd for HER2-low tumours.